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Mutations in DNAH1, Which Encodes an Inner Arm Heavy Chain Dynein, Lead to Male Infertility from Multiple Morphological Abnormalities of the Sperm flagella

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Mutations in DNAH1, Which Encodes an Inner Arm Heavy Chain Dynein, Lead to Male Infertility from Multiple Morphological Abnormalities of the Sperm flagella View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by HAL Descartes Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella. Mariem Ben Khelifa, Charles Coutton, Raoudha Zouari, Thomas Karaouz`ene, John Rendu, Marie Bidart, Sandra Yassine, Virginie Pierre, Julie Delaroche, Sylviane Hennebicq, et al. To cite this version: Mariem Ben Khelifa, Charles Coutton, Raoudha Zouari, Thomas Karaouz`ene,John Rendu, et al.. Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella.. American Journal of Human Genetics, Elsevier (Cell Press), 2014, 94 (1), pp.95-104. <10.1016/j.ajhg.2013.11.017>. <pasteur-01061012> HAL Id: pasteur-01061012 https://hal-riip.archives-ouvertes.fr/pasteur-01061012 Submitted on 4 Sep 2014 HAL is a multi-disciplinary open access L'archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destin´eeau d´ep^otet `ala diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publi´esou non, lished or not. The documents may come from ´emanant des ´etablissements d'enseignement et de teaching and research institutions in France or recherche fran¸caisou ´etrangers,des laboratoires abroad, or from public or private research centers. publics ou priv´es. REPORT Mutations in DNAH1, which Encodes an Inner Arm Heavy Chain Dynein, Lead to Male Infertility from Multiple Morphological Abnormalities of the Sperm Flagella Mariem Ben Khelifa,1,2,3,15 Charles Coutton,1,2,4,15 Raoudha Zouari,5 Thomas Karaouze`ne,1,2 John Rendu,1,6,7 Marie Bidart,1,7 Sandra Yassine,1,2 Virginie Pierre,1,2 Julie Delaroche,1,7 Sylviane Hennebicq,1,2,8 Didier Grunwald,1,7 Denise Escalier,9 Karine Pernet-Gallay,1,7 Pierre-Simon Jouk,10,11 Nicolas Thierry-Mieg,10 Aminata Toure´,12,13,14 Christophe Arnoult,1,2,16 and Pierre F. Ray1,2,6,16,* Ten to fifteen percent of couples are confronted with infertility and a male factor is involved in approximately half the cases. A genetic etiology is likely in most cases yet only few genes have been formally correlated with male infertility. Homozygosity mapping was carried out on a cohort of 20 North African individuals, including 18 index cases, presenting with primary infertility resulting from impaired sperm motility caused by a mosaic of multiple morphological abnormalities of the flagella (MMAF) including absent, short, coiled, bent, and irregular flagella. Five unrelated subjects out of 18 (28%) carried a homozygous variant in DNAH1, which encodes an inner dynein heavy chain and is expressed in testis. RT-PCR, immunostaining, and electronic microscopy were carried out on samples from one of the subjects with a mutation located on a donor splice site. Neither the transcript nor the protein was observed in this individual, confirming the pathogenicity of this variant. A general axonemal disorganization including mislocalization of the microtubule doublets and loss of the inner dynein arms was observed. Although DNAH1 is also expressed in other ciliated cells, infertility was the only symptom of pri- mary ciliary dyskinesia observed in affected subjects, suggesting that DNAH1 function in cilium is not as critical as in sperm flagellum. Male infertility affects more than 20 million men world- mainly composed of an intricate network of microtubules wide and represents a real health concern.1 It is a typical and dyneins. Sperm parameters have not been systemati- multifactorial disorder with a strong genetic basis and cally explored and are often only scarcely described additional etiological factors such as urogenital infections, in manuscripts investigating PCD-affected individuals. immunological or endocrine diseases, attack from reactive Although sperm flagella and motile cilia have a similar oxygen species (ROS), or perturbations from endocrine axonemal structure based on the presence of nine periph- disruptors. To date, despite substantial efforts made to eral microtubule doublets plus two central ones, they pre- identify genes specifically involved in male infertility by sent several differences that might explain why PCDs are many teams including ours,2,3 only a handful of genes not always associated with asthenozoospermia.4 We note have been formally correlated with human sperm defects. that no mutations in axonemal genes have been described Male infertility caused by impaired sperm motility (asthe- as being involved exclusively in infertility without also nozoospermia) is also often observed in men with primary inducing PCD. ciliary dyskinesia (PCD), a group of mainly autosomal- In the present study, we analyzed 20 subjects presenting recessive disorders caused by dysfunctions of motile cilia with asthenozoospermia resulting from a combination of leading primarily to respiratory infections and often to five morphological defects of the sperm flagella (absent, situs invertus. Recent research on PCD has been extremely short, bent, and coiled flagella and flagella of irregular prolific and allowed the identification and characterization width) without any of the other PCD-associated symp- of numerous proteins necessary for adequate axonemal toms. Similar phenotypes have been previously described molecular structure and assembly (Table S1 available and named ‘‘dysplasia of the fibrous sheath,’’ ‘‘short tails,’’ online). The axoneme is a highly evolutionarily conserved or ‘‘stump tails.’’5–15 We propose to call this syndrome structure found in motile cilia and in sperm flagella, ‘‘multiple morphological anomalies of the flagella 1Universite´ Joseph Fourier, Grenoble 38000, France; 2Laboratoire AGIM, CNRS FRE3405, Equipe ‘‘Andrologie et Ge´ne´tique,’’ La Tronche 38700, France; 3Laboratoire de ge´nomique Biome´dicale et Oncoge´ne´tique, Institut Pasteur de Tunis, 1002 Tunis, Tunisie; 4CHU de Grenoble, Hoˆpital Couple Enfant, De´partement de Ge´ne´tique et Procre´ation, Laboratoire de Ge´ne´tique Chromosomique, Grenoble 38000, France; 5Clinique des Jasmins, 23, Av. Louis BRAILLE, 1002 Tunis, Tunisia; 6CHU de Grenoble, Institut de Biologie et Pathologie, De´partement de Biochimie, Toxicologie et Pharmacologie (DBTP), UF de Biochimie et Ge´ne´tique Mole´culaire, Grenoble 38000, France; 7INSERM, U836, Grenoble Institute of Neuroscience, La Tronche 38700, France; 8CHU de Grenoble, Hoˆpital Couple Enfant, De´partement de Ge´ne´tique et Procre´ation, Laboratoire d’Aide a` la Procre´ation – CECOS, Grenoble 38000, France; 9INSERM UMR_S933, Universite´ Pierre et Marie Curie (Paris 6), Paris 75012, France; 10Universite´ Joseph Fourier-Grenoble 1 / CNRS / TIMC- IMAG UMR 5525, Grenoble 38041, France; 11CHU de Grenoble, Hoˆpital Couple Enfant, De´partement de Ge´ne´tique et Procre´ation, Service de Ge´ne´tique Clinique, Grenoble 38000, France; 12INSERM, U1016, Institut Cochin, Paris 75014, France; 13CNRS, UMR8104, Paris 75014, France; 14Universite´ Paris Descartes, Sorbonne Paris Cite´, Faculte´ de Me´decine, Paris 75014, France 15These authors contributed equally to this work 16These authors contributed equally to this work and are co-senior authors *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ajhg.2013.11.017. Ó2014 by The American Society of Human Genetics. All rights reserved. The American Journal of Human Genetics 94, 95–104, January 2, 2014 95 (MMAF),’’ a name that provides a more accurate descrip- the axoneme and that its depletion alters motility.17 The tion of this phenotype. We carried out a SNP whole- second subregion in chromosome 3 includes 28 genes genome scan on 20 individuals presenting with severe (Table S2). The dynein heavy chain 1 gene (DNAH1 MMAF. The study was approved by our local ethics com- [MIM 603332]) appeared as the best candidate gene mittee; all individuals gave their signed informed consent because it codes for an axonemal dynein heavy chain and national laws and regulations were respected. All indi- and is expressed in various tissues including testis.18 viduals originated from North Africa (11 Tunisians, 7 Furthermore, asthenozoospermia was described in mice Algerians, and 2 Libyans) and were treated in Tunis (Clin- lacking Dnahc1, the DNAH1 mouse ortholog (previously ique des Jasmins, Tunis, Tunisia) for primary infertility. named Mdhc7).19 Finally, among the ten genes located Twelve of the subjects were born from related parents, in the selected region of chromosome 20 (chr20: usually first cousins. None of the subjects were related to 33,572,687–34,070,415), only SPAG4 (MIM 603038) ap- one another apart from three individuals (P1–P3) who peared as a good candidate: it was described in rat to be were brothers. All subjects had normal somatic karyotypes. associated with the axoneme in elongating spermatids All sperm analyses were performed at least twice, in and epididymal sperm.20 We therefore decided to sequence accordance with the World Health Organization recom- KIF9 (RefSeq accession number NM_001134878.1), mendations.16 Subjects were recruited on the basis of the DNAH1 (RefSeq NM_015512.4), and SPAG4 (RefSeq identification of >5% of at least four of the aforemen- NM_003116.1). tioned flagellar morphological abnormalities (absent, We sequenced the 12 exons and the intron boundaries short, coiled, bent, and irregular flagella) (Table 1). All of SPAG4 in the 13 individuals homozygous at this locus, subjects presented with severe asthenozoospermia: 11 and the 19 exons and intron
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